Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and a devastating movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Approximately 90-95% of PD cases are sporadic and pesticides have been implicated in sporadic PD etiology. Paraquat (PQ) is a widely used herbicide and many epidemiology studies have associated PQ exposure with increased PD risk. Mechanistic controversy exists regarding the DA neurotoxicity of PQ, as the mechanisms through which PQ impacts the brain and the resulting neuropathology remains a point of debate. Importantly, PD is linked to peripheral and brain immune perturbation. Microglia, the resident innate immune cells in the brain, are chronically activated in PD. As a source of neurotoxic cytokines and reactive oxygen species, chronic microglial activation and neuroinflammation have been implicated in the initiation and augmentation of selective DA neurotoxicity in PD models in vivo and in vitro. The paraquat neuroimmune hypothesis holds that microglia and neuroinflammation are culpable in PQ DA neuropathology. Paraquat activates microglia both in vivo and in vitro, where research has shown that the reduction of pro-inflammatory factors ameliorates PQ DA neuropathology. Despite low levels of PQ localized in the brain, previous research has predominantly focused on the direct interaction of PQ with brain parenchymal cells, the neurons and glia. Importantly, PQ accumulates prominently in the lung, kidney, and liver with toxicity. Here, we propose that peripheral damage from PQ signals to the brain through circulating damage associated molecular patterns (DAMPs) to exert deleterious central nervous system (CNS) effects. Preliminary data implicate an important role for the circulating DAMP HMGB1 in how PQ impacts the brain. Thus, we hypothesize that PQ exposure causes circulating HMGB1, which causes neuroinflammation and DA neuropathology. As such, our specific AIMS are to: AIM1) Assess the role of HMGB1 in PQ?induced neuroinflammation & neuropathology; AIM2) characterize the role of vascular endothelial cells and brain capillaries in PQ-induced HMGB1 and neuroinflammation; AIM3) Define the role of myeloid cells in PQ-induced neuroinflammation and neuropathology. If successful, these findings will reveal a novel peripheral mechanism of pesticide (PQ)- induced CNS effects, implicate HMGB1 as a potential therapeutic target for chronic CNS effects after PQ/pesticide exposure, and provide key insight into the role of the periphery in PD.